Alpha interferons are used widely for the treatment of a variety of haematological malignancies including hairy cell leukaemia, chronic myelogenous leukaemia, low grade lymphomas, cutaneous T-cell lymphomas, and solid tumours such as renal cell carcinoma, melanoma, carcinoid tumours and AIDS-related Kaposi's sarcoma (Gutterman, J. U., Proc. Natl. Acad. Sci. USA, 1994 91: 1198-1205). Antitumour effects are usually seen at high dosage levels, often of the order of tens of millions of units of interferon-.alpha. (IFN-.alpha.), administered by parenteral injection. Interferon-.beta. (IFN-.beta.) is licensed for clinical use in treatment of relapsing-remitting multiple sclerosis and chronic viral hepatitis B and C.
Interferon-.alpha. and Interferon-.beta. are both Type I interferons. Type I interferons are a large class of naturally-occurring cytokines which includes over 16 subclasses of IFN-.alpha., plus IFN-.beta. and IFN-.omega.. The Type I interferons bind to a single cell surface receptor, and stimulate a complex sequence of signal transduction events leading ultimately to anti-viral, anti-proliferative and other immunomodulatory effects, cytokine induction, and HLA class I and class II regulation (Pestka et al., Annu. Rev. Biochem., 1987 56: 727). Individual subtypes of Type I IFN vary in activity. The most frequently observed amino acid at each position has been identified by scanning of a large number of allelic subtypes of IFN-.alpha., and a synthetic Type I interferon having the consensus sequence has been synthesized (Alton et al in "The Biology of the Interferon System", E. de Maeyer and H. Schellekens eds. Elsevier (1983) 1991-128). This consensus interferon is commercially available (Infergen; Amgen, Inc.), and has recently been shown to have higher activity (w/w) than IFN-.alpha.2a or IFN-.alpha.2b; it has been suggested that consensus IFN would be clinically superior to IFN of an individual natural subtype (Blatt et al, J. Interferon and Cytokine Research, 1996 16: 489-499).
Although a number of routes of administration, including intravenous, subcutaneous, intramuscular, topical, and intralesional injection, are commonly employed for the administration of type I interferons, the oral route has not been generally used, because interferons are proteins which are considered to be inactivated by proteolytic enzymes and which are not absorbed appreciably in their native form in the gastrointestinal tract. Indeed a number of studies have failed to detect interferons in the blood following oral administration (Cantell and Pyhala, J. Gen. Virol., 1973 20: 97-104; Wills et al, J. IFN Res., 1984 4: 399-409; Gilson et at, J. IFN Res., 1985 5: 403-408).
It is widely considered that in order to obtain the maximum therapeutic effect, the highest possible dose of interferon should be used. Although the availability of recombinant material has meant that very high dose levels are feasible, in practice it has been found that the side-effects of interferon administration have severely limited the dose of interferon which can be used and the duration of treatment. These side-effects include severe malaise and depression, leading in some cases even to suicide. A recent editorial by Hoofnagle in the New England Journal of Medicine has summarized these problems (Hoofnagle, J. H., and Lau, D., New Eng. J. Medicine 1996, 334:, 1470-1471). Meta-analysis of the effect of interferon-.alpha. treatment in patients with hepatitis B e antigen-positive chronic hepatitis B has shown a rate of remission of 25 to 40%, in patients with typical chronic hepatitis B, treated with 5 million IU daily or 10 million IU three times per week for 3 to 6 months. These results fall short of a cure, however, as most patients remain positive for hepatitis surface antigen and harbour viral DNA when tested by the polymerase chain reaction. Furthermore, these doses of interferon are poorly tolerated, and 10% to 40% of patients require dose reduction due to intolerable side effects. At a well-tolerated dose of 1 million IU daily, the remission rate is, however, only 17% (Perrillo et al. New Eng. J. Medicine, 1990, 323:, 295-301). In patients with chronic hepatitis C, sustained long-term improvement is associated with the loss of HCV RNA, which occurs in only 10 to 20% of patients treated with a dose of 3 million IU three times per week for 6 months (Hoofnagle and Lau, op. cit.). In patients with cancer, significant response rates are usually seen only at the highest tolerated doses of interferon-.alpha.. Thus in patients with multiple myeloma, for example, the response rate is 50% in patients treated with 20 to 30 million IU daily, and only 15 to 20% in patients treated with 3 million IU. Very few patients are able, however, to tolerate the high-dose regimen for more than a short period of time (Ahre et al. Eur. J. Hematol., 1988, 41:, 123-130). Thus clearly there is a need in the art for means which would enable the administration of high dose interferon without the induction of severe side-effects.
There have been a number of anecdotal reports of efficacy of low doses of interferon administered as a nasal spray or as an oral liquid formulation in the treatment of a variety of viral conditions, particularly influenza. However, in most of these reports the interferon preparations used were relatively crude. Placebo-controlled trials of relatively high dose intranasal interferon for treatment of rhinovirus infection showed that the treatment was effective, but that there was a significant incidence of side-effects (Hayden et al, J: Infect. Dis., 1983 148: 914-921; Douglas et al, New Engl. J. Med., 1986 314: 65-80; Hayden et al, New Engl. J. Med., 1986 314: 71-75).
More recently a series of patent specifications has described the use of low doses of orally administered interferon of heterologous species origin for the treatment of infectious rhinotracheitis ("shipping fever") in cattle, and of feline leukaemia, and also treatment of other conditions, for enhancement of efficiency of vaccines; for improving the efficiency of food utilisation; and for prevention of bovine theileriosis. See U.S. Pat. No. 4,462,985, Australian Patent No. 608519, Australian Patent No. 583332 and U.S. Pat. No. 5,215,741 respectively. In addition U.S. Pat. No. 5,017,371 discloses the use of interferon in this way for treatment of side-effects of cancer chemotherapy or radiotherapy. In these specifications, the interferon used was human interferon-.alpha. prepared by the method of Cantell, administered in phosphate buffered saline, at a dose of 0.01 to 5 IU per pound body weight. While these specifications suggest that such low doses of interferon administered to the oropharyngeal mucosa, preferably in a form adapted for prolonged contact with the oral mucosa, may be efficacious for treatment of a wide variety of conditions including cancer, the experimental evidence for conditions other than shipping fever, feline leukaemia, canine parvovirus and theileriosis is largely anecdotal. In particular, no properly controlled trials of this treatment in any animal model for human cancers are presented.
More recent studies on the effects of very low doses of interferon administered by the oral or oropharyngeal mucosa have been reviewed (Bocci, Clin. Pharmacokinet., 1991 21: 411-417; Critic. Rev. Therap. Drug Carrier Systems, 1992 9: 91-133; Cummins and Georgiades, Archivum Immun. Therap. Exp., 1993 41: 169-172). It has been proposed that this type of treatment is particularly useful for treatment of HIV infection, and can at least improve quality of life in AIDS patients (Kaiser et al, AIDS, 1992 6: 563-569; Koech et al, Mol. Biol. Ther., 1990 2: 91-95). However, other reports indicate that such treatments provide no clinical benefit. A Phase I study of use of oral lozenges containing low doses of interferon for treatment of hepatitis B has also been reported (Zielinska et al, Archiv. Immunol. Therap. Exp., 1993 41: 241-252).
In Australian Provisional Patent Application No. PN 9765, low doses of interferon administered to the oropharyngeal cavity by the oromucosal route were shown to be effective in protecting mice against challenge with highly metastatic tumour cells (Friend Erythroleukemia). The quite exceptional nature of these results, together with the fact that very few substances exhibit activity against these very aggressive tumours, indicates that administration of interferon to the oropharyngeal cavity may be useful in the treatment of cancer. Low oromucosal doses of interferon were also effective in treating mice injected intraperitoneally with encephalomyocarditis virus (EMCV), which normally gives rise to a rapidly progressing fatal disease characterized by central nervous system involvement and encephalitis. Although this system is a very severe test of antiviral activity, the oromucosal route for administration of interferon was comparably effective to intraperitoneal administration.
The disclosure of all patents and publications referred to in this specification are incorporated by reference herein.